It has become clear that an internal death program controls the number and types of immune cells in the body. Diseases can result from inefficient lymphocyte death or from inappropriate or excessive death such as is caused by the human immunodeficiency virus (HIV) during AIDS. In this project we are taking a multifaceted approach to studying molecular mechanisms of this death program in lymphocytes. Our attack is based on the model of a cell surface receptor called CD95/Fas/APO-1 that can play an important role in stimulating the death of immune cells. We are trying to understand how this receptor stimulates the intracellular machinery that causes cellular demise. In particular we have focused on the activation of a protease termed Flice/Mach1 (caspase 8) which can directly carry out the death program. These studies will help us to determine how cells can initiate their own death whose regulation may play a role in various diseases ranging from autoimmune conditions to infectious diseases such as AIDS. Following infection with HIV, a critical effect in the onset of AIDS is believed to be death of T lymphocytes caused by the virus. We would like to determine why the virus triggers the death of T cells.